Drugs for Cardiovascular Disease

Question 1

Lecture Outcomes

Answer 1

1) describe the basic features of the two broad categories of disorders affecting the
human cardiovascular system.
2) describe the main symptoms and pathobiological basis of angina.
3) describe the key historical events and circumstances surrounding the development
of nitroglycerin as an effective but flawed angina remedy.
4) describe the mechanisms underlying the anti-angina properties of nitroglycerin
5) explain the rationale for and clinical trial outcomes of mass prescription of
polypills containing multiple cardiovascular drugs in low and moderate income
countries.
6) explain the role of genetics in variable patient responses to cardiovascular
medicines and the potential clinical implications.

Question 2

Aims of Lecture

Answer 2

1) To explore how discovering the
antianginal properties of nitroglycerin
inspired the development of many
drugs for cardiovascular disease.
2) To explore the role of genetics in
variable responses to cardiovascular
drugs.

Question 2

Types of Cardiovascular Disease (CVD)

Answer 2

1. CVDs due to atherosclerosis:
    Ischaemic heart disease or coronary artery disease
   (i.e., basis for “heart attacks”)
    Cerebrovascular disease (i.e., basis for strokes)
    Diseases of the aorta and arteries, including
   hypertension and peripheral vascular disease.
2. Other CVDs
   
   Congenital heart disease
    Rheumatic heart disease
    Cardiomyopathies
    Cardiac arrhythmias

Question 2

CVD in Australia – 2022 Snapshot (ABS Data)

Answer 2

 5.2% or 1.3 million people had heart, stroke and vascular disease
 ↑ from 4.1% in 2001 but similar to 2007–08 (5.3%)
 CVD slightly more common in males than females (5.9% c.f. 4.6%).
 Prevalence strongly ↑ with age
 Heaviest toll in low socioeconomic and regional populations

Question 3

Angina – What is it?

Answer 3

Spasmodic bouts of intense discomfort in
upper chest
Pain often radiates to left arm
Sense of suffocation and impending death
Can be stable (predictable frequency,
provoked by exercise, excitement, etc) or
unstable (unpredictable without
provocation)
Can precede heart attack (“preinfarction’)

Question 4

The Causes of Angina: Myocardial
Oxygen (O
2) Deprivation

Answer 4

 Angina occurs when low blood flow (myocardial
ischemia) limits O2 delivery to heart muscle during
exertion
 Atherosclerotic narrowing of coronary artery is main
cause (i.e. block in blood vessels which supply heart
muscle)
 Involves fatty deposits (“plaques”) in blood vessel
(“atherosclerosis”)
 Angina can reflect other causes (e.g. anaemia (low
haemoglobin), hypotension (low BP), endothelial
damage, etc)

Answer 5

Question 5

1847: Ascanio Sobrero - Inventor of Nitroglycerin

Answer 5

Chemistry Professor in Turino, Italy
Face badly scarred in lab explosion
Invented nitroglycerin using glycerol and
mineral acids (needed to chill the reaction!)
Considered it too dangerous to be of
practical use
(“When I think of all the victims killed… I am
almost ashamed to admit to be its
discoverer.”)

Question 6

Alfred Nobel Tames the Monster

Answer 6

1864, Nobel family company began selling
nitroglycerin to mining companies
‘64, explosion at Stockholm plant killed
Alfred’s brother (5 in total)
’66-’68, nitroglycerin kills scores of people
around the world

Alfred finds nitroglycerin is stable if
blended with porous silica gel
(“Dynamite” putty)
 Invented patented detonator
which made him a massive
fortune

Question 7

“Monday Disease” Afflicted 19th C Workers in TNT
Munitions Plants

Answer 7

Munitions factory workers exposed to large
quantities of nitroglycerin
Strong headaches & facial flushing on return
to work after weekend break
i.e., persistent vasodilatation during working week
Some workers solved situation by wearing
work clothes on weekend
Suggested that nitroglycerin residues in the
worker’s overalls were producing chronic
vasodilatation

Question 8

1879 - Murrell’s First Human Trials

Answer 8

Tested nitroglycerin on 35 healthy
individuals
Considerable variability in response
“From a consideration of the
physiological action of the drug… I
concluded that it would probably prove
of service in the treatment of angina
pectoris, and I am happy to say this
expectation has been realised.”
Used early BP monitoring device to confirm
beneficial effects in 3 angina patients

Question 8

William Murrell – 19th C Pioneer in Angina Treatment

Answer 8

Noted English doctor born in London in 1853
 Trained in medicine alongside Sydney Ringer (notable
early pharmacologist)
1877, Physician at Westminster Hospital, London
Aware of conflicting literature reports concerning
nitroglycerin & headaches
Aware of use of amyl nitrate in angina by Lauder
Brunton
Wondered if nitroglycerin would be of value in angina
patients

Question 9

Murrell’s Famous Self-Experiment

Answer 9

“I obtained some 1% solution. One afternoon, whilst
seeing out-patients, I remembered that I had a little
bottle in my pocket. Wishing to taste it, I applied the
moistened cork to my tongue, and a moment after, a
patient coming in, I had forgotten all about it.

“I had not asked my patient half a dozen questions before I felt a violent
pulsation in my head. The pulsation rapidly increased, and soon became
so severe that each beat of the heart seemed to shake my whole body.”

Question 10

Nitroglycerin in Modern Medicine

Answer 10

Widely used to relieve angina pain in vulnerable
patients
Acts by dilating veins in periphery
“Preloading” decreases amount of blood
returned to heart
Peripheral “pooling” reduces effort needed by
ventricles to pump blood into circulation
Reduces workload on heart muscle (less severe
angina pain)
Other organic nitrates also used

Question 11

Nitroglycerin is Taken Via Non-Oral Routes

Answer 11

Nonoral means pills are not swallowed (drug breaks down in stomach acid)
Used via various topical routes (oral cavity in acute attack)

Other routes: sticking patches (for skin application), oral sprays, oral pastes,
intradermal implants
Tablet, patches removed once pain subsides (avoid headaches)

Sublingual (under tongue)
Buccal (against cheek)

Question 12

How Does Nitroglycerin Work?

Answer 12

Answer 13

Answer 14

Answer 14

Question 14

Ongoing Challenges - 1: The Global Problem & Promise of Polypills

Answer 14

 ≈80% of global CVD in LMICs (Low + Middle Income Countries)
 Low-income: <$1,005 GNI per capita
 Lower-middle-income: $1,006 to $3,955 GNI
 Less resources for public health
 Growing interest in using polypills
 Polypill = Fixed dose combinations of well tolerated (modest)
doses of several CV drugs, e.g.:
 Statins to lower cholesterol
 β-Blockers to reduce strength of heart beats
 ACE Inhibitors to increase blood vessel diameters
 Aspirin to lower risk of blood clotting
 Given to everyone in population (e.g., > 55’s, etc) in hope of
↓ strokes & heart attacks

Question 15

The PolyIran Study – Evidence for Polypill Effectiveness

Answer 15

 Roshandel et al., 2019, first results from large population
polypill “cardioprotection” study
 Randomised trial in NE Iran (Golestan Province)
 6838 participants selected on basis of age (50–75 yrs)
 Almost 90% had no previous CVD
 Equal mix of male/females
 The 4-drug polypill used contained:
 2 half-dose blood pressure-lowering drugs
 A moderate-intensity dose of a statin
 Low-dose aspirin
 Findings: ↓ ↓ in major CVD events over 5 yr
 Adjusted hazard ratio [HR] was 0·66, 95% CI 0·55–0·80
 Only 13% of participants discontinued the polypill
 Suggests polypill approach is safe & effective

Question 16

Ongoing Challenges – 2: Variability in Patient Response

Answer 16

Any two patients rarely respond identically to the same dose of a drug
 This variability is obvious with cardiovascular drugs
 i.e., “Mean” responses in populations can be misleading
 Some patients gain little benefit, while others show exaggerated responses or toxicity
Holds true across many drug classes (e.g., statins, diuretics, anticoagulants)

Answer 16

Answer 16

Answer 17

Answer 18

Answer 19

Question 20

Conclusion: Can “Personalised Medicine” Improve CV Disease
Treatment Outcomes – Hope or Hype?

Answer 20

Hope:
 Rising availability of genetic screening technology (e.g., PCR, Next-Gen
sequencing) will see  adoption in medicine
 Knowing a person’s SNVs may guide choice of CV drugs that work
better or are safer in that patient
Hype:
 Who pays for the testing or research to validate disease associations?
 Individual, health insurer?
 Is it worth the effort? (likely depends on disease context – nature of CV
disease)
 Doctors often switch to drugs with less “pharmacogenetic issues”
 Which profession will steward the knowledge required to
implement pharmacogenomic knowledge?
 Doctors, pharmacists, scientists?

Question 20

Statins – A lifesaving drug! - Lecture overview

Answer 20

• What are statins used for and what did we do before we had statins?
• How were statins developed?
• How do statins work?
• What are the benefits and risks of taking a statin?
• Where are we going with statin therapy now?

Question 20

Lecture learning outcomes

Answer 20

• describe cardiovascular disease and its causes
• describe the normal role of cholesterol in human body and the production
  and source of cholesterol
• relate the lipid hypothesis to the role of cholesterol in cardiovascular
  disease and the development of statins
• describe the lipid-lowering action of statins and additional benefits of statin
  therapy
• list statin-related side effects
• describe the action of ezetimibe and PCSK9 inhibitors as alternative lipidlowering therapies

Question 20

Cardiovascular disease

Answer 20

• Cardiovascular disease is the leading cause of death & disability in the world.
• Refers to conditions that effect the structure and function of the heart &
  vessels and includes:
• Coronary heart disease (CHD)
• Coronary artery disease (CAD)
• Heart failure
• Valve disease
• Arrhythmias
• Peripheral artery disease (PAD)
• Cerebrovascular disease
• Has both lifestyle and genetic components
• Can lead to lifelong chronic health problems

Question 21

Causes of CVD

Answer 21

• Cardio and vascular diseases share common risk factors
• Genetic risk factors:
• Defects in receptors that clear cholesterol
• Defects in genes that regulate fluid control/salt balance
• Defects in genes that sense pressure changes in vessels
• Lifestyle risk factors:
• Age
• Male gender (risk is similar after menopause)
• Family history
• High blood pressure
• High cholesterol
• Overweight/obese
• Physically inactive
• Smoking
• Poor diet
• Excessive alcohol consumption
• Glucose intolerance/insulin resistance/metabolic syndrome/type 2 diabetes

Question 22

History of cholesterol & CVD – “The Lipid Hypothesis”

Answer 22

• > 100 years ago - German pathologist Virchow observed artery walls of patients dying from occlusive vascular disease were thick and irregular and
  contained a yellowish fatty substance (atheroma = Greek for porridge).
• 1913 – Anitschkow & Chalatow showed that feeding cholesterol to rabbits
  produced atheromas.
• Physicians remain skeptical because patients with CVD had cholesterol levels
  similar to the general population.
• 1950s – Framingham study: confirmed link between high cholesterol and increased risk of CVD.
• Confirmed in many other studies & populations.
• Later studies confirmed it was predominately due to LDL-c levels.
• Lipid Hypothesis: Elevated LDL-c is causally related to coronary artery disease
  & reducing it will reduce the risk of myocardial infarction & other coronary
  events

Question 23

How can we reduce LDL – early attempts & Cholesterol Controversy Phase 1

Answer 23

• Lipid Hypothesis remained controversial due to lack of studies demonstrating
  benefits with reduction in cholesterol/LDL.
• Early dietary & lifestyle studies demonstrated some benefits, which were
  compelling when viewed together, but less so individually.
• Dietary changes in Western countries are difficult to maintain – small reductions.
• Why…cholesterol is also made by the body – what happens when it makes too much?
• Other drugs – bile acid sequestrants, fibrates, niacin & probucol – limited efficacy &/or tolerability.
• Drugs targeting the biosynthesis of cholesterol were investigated & developed.

Question 23

What is cholesterol?

Answer 23

• Cholesterol is a fat-like substance that is essential for the normal
  functioning of the body.
• It is required to make some hormones and vitamin D, maintain normal
  cellular structure & function, and to assist in digesting food.
• The body produces cholesterol naturally, but we also get it from food.
• Cholesterol (and other lipids) are transported around body via
  lipoproteins:
• Low-density lipoprotein (LDL) – “bad” cholesterol – ~70% of cholesterol
• High density lipoprotein (HDL) – “good” cholesterol
• Triglycerides - fat
• Lipoprotein (a) – an LDL-like particle
• Many others – VLDL, IDL, etc etc

Question 24

Different classes of statins

Answer 24

Answer 24

Question 24

Cholesterol biosynthesis

Answer 24

• Most mammalian cells produce cholesterol.
• Complex process involving >30 enzymes.
• Synthesis pathway was discovered 1950s/60s
• Earliest drug to target this pathway was triparanol – which acts late in the pathway – withdrawn due to
  development of cataracts, thought to be due to
  accumulation of desmosterol.
• HMG-CoA reductase was then targeted:
• First & rate-limiting step in cholesterol synthesis.
• Its precursor HMG-CoA is water soluble and has other
  breakdown pathways.
• It’s inhibition limits build up of potentially toxic
  precursors.

Question 25

Lovastatin enters clinical use

Answer 25

• Physicians started prescribing the drug from 1987 onwards
• At its maximal dose of 80mg/day was shown to reduce LDL
  levels by up to 40% with minimal adverse effects.
• Went on to achieve peak annual sales of US $1 billion
• Many more followed:
• 1988 – simvastatin (semi-synthetic derivative of lovastatin)
• 1991 – pravastatin (derived from biotransformation of compactin)
• 1994 – fluvastatin (synthetic)
• 1997 – atorvastatin (synthetic)
• 1998 – cerivastatin (synthetic)
• 2003 – rosuvastatin (synthetic)

Question 25

Different classes of statins

Answer 25

• Active component is a modified 3,5-dihydroxy-glutaric acid moiety
  (structurally similar to HMG-CoA).
• Statin must have a 3R,5R configuration to competitively bind to HMG-CoA
  reductase.
• Molecular & clinical differences arise due to the side ring.
• Substituents on the side ring define the solubility and pharmacological
  properties
• Pharmacokinetic properties arise from solubility & form administered in
  (inactive lactone v active acid form)

Question 26

Drugs targeting HMG-CoA reductase

Answer 26

• 1970s
• ML236B or compactin (mevastatin) was identified by Japanese microbiologist Akira Endo in a fermentation broth of Penicillium citrinum.
• Demonstrated to lower plasma cholesterol in rabbit, monkey & dog (but not rat)
• Developed by Sankyo and shown to be highly effective at lowering TC and LDL in patients with FH
• 1978
• Albert & Chen at Merck Research Labs discovered mevinolin (lovastatin) in fermentation broth of Aspergillus terreus.
• 1980
• In April, after animal safety studies, trials of lovastatin in healthy humans began and were shown to lower LDL.
• In September, mevastatin was withdrawn from the market & trials stopped by Sankyo – reasons never made public – speculated to be related to serious animal toxicity
• Due to close structural similarity with lovastatin, Merck stopped all their human trials and went back to animals
• 1982
• Small studies in humans with severe FH restarted with lovastatin (outside Merck) and showed clear reductions in LDL with
  very few adverse effects
• 1983
• With additional animal safety studies confirming no toxicity, Merck restarted human trials of lovastatin
• 1984
• Multiple studies in different populations demonstrated benefits of lovastatin with very few adverse effects
• 1986
• Merck applies for regulatory approval for lovastatin, which after considerable review by the FDA was granted in August
  1987

Question 27

Cholesterol Controversy Phase 2

Answer 27

• Late 80s/early 90s – movement of treating hypercholesterolaemia came under fire again.
• Largely because clinical trial evidence was limited to middle-aged men – did it also apply to women & the elderly?
• 1990 & 1992 review of pre-statin trials suggested while CHD events were reduced, survival was not improved… off- set by increase in non-cardiac mortality (specifically cancer & violence-related)..?
• Expert panels in Europe & USA continued to recommend cholesterol-lowering drugs, but other countries (Britain & Scandinavia) rejected.

Answer 27

Question 27

So how do statins actually work?

Answer 27

Question 28

Other benefits of statin therapy

Answer 28

• Statins now thought to have a range of non-lipid
  related pleiotropic effects, including
• Improving vascular function
• Stabilising atherosclerotic plaques
• Anti-inflammatory effects
• Immunomodulatory effects
• Ant-thrombotic effects
• Effects on bone metabolism
• Reduced risk of dementia
• These additional benefits are thought to be due
  to inhibition of isoprenoid intermediates of the
  mevalonate pathway
• Should we put statins in the drinking water?

Question 29

Statins & Heart Disease – where we stand now?

Answer 29

• Now overwhelming evidence to support causal link between elevated LDL and CVD outcomes &
  mortality
• Statins are the most widely prescribed & evidence-based lipid-lowering drug in the world for
  lowering LDL and reducing cardiovascular morbidity & mortality
• For every 1 mmol/L reduction in plasma LDL – associated with a 22% reduction in major coronary and vascular events
• Studies support both the early & prolonged use of statins in a range of patient populations and in
  both primary & secondary prevention
• WOSCOPS study
• 4S Study
• Heart Protection Study
• Cholesterol Treatment Trialists Collaboration
• Jupiter Study
• In addition to lifestyle modification, statins are the bedrock of all international guidelines on lipid
  management.

Question 30

Statins therapy – are there any risks?

Answer 30

• All drugs – even “natural therapies” come with a risk of side effects!
• Most common statin-related side effect (~70% of reported) is muscle related – statin associated muscle symptoms or SAMS
• Other side effects include:
• New on-set type 2 diabetes
• Neurological & neurocognitive effects
• Hepatotoxicity
• Renal toxicity
• Other conditions
• True prevalence of statin intolerance is widely debated & currently no universal
  definition – especially with respect to SAMS
• Number of underlying causes that may contribute to statin toxicity/side effects.

Answer 30

Question 31

Risk factors associated with SAMS

Answer 31

Question 31

Prevalence of statin intolerance & its risk factors

Answer 31

Question 31

Other causes of statin intolerance

Answer 31

Question 31

ABC Catalyst Oct 2013 – Heart of the matter

Answer 31

• On 24 and 31 October 2013, ABC aired a two-part special edition of Catalyst, title Heart of the matter that
  was critical of statins.
• Program questioned the link between high cholesterol levels and cardiovascular disease and suggested the
  benefits of statins had been overstated and the harms downplayed.
• Nearly 1.5 million Australians are estimated to have viewed each part of the program
• Program advised its content should not be taken as medical advice – still widely criticized & ultimate retracted.
• In the weeks following the program
• 2.6% reduction in statin dispensing = 14,005 fewer dispensing Australia wide EVERY week (higher in people not taking
  other CVD medication)
• 28.8% increase in the discontinuation of statin use
• At 30 June 2014 (8 months later) - >60,000 people affected and no sign that this had abated
• This could represent 1522 and 2900 preventable and potentially fatal major vascular events
• Remember in Australia – 1 person has a cardiovascular event every 12 minutes!

Question 32

Statin-associated muscle symptoms - SAMS

Answer 32

• Accounts for 70% of all reported statin side
  effects
• SAMs usually presents as bilateral condition of
  the large proximal muscles, particularly of lower
  extremities.
• Symptoms can occur at rest or shortly after
  exercise, usually within 1 month of treatment
  initiation or increase in dose
• Can occur with and without increases in serum
  creatine kinase
• Can be classed as toxic or immune related
  (HMG-CoA reductase antibodies)
• Resolves with cessation of statin therapy

Question 32

Mechanisms of statin toxicity

Answer 32

Question 32

How common is statin intolerance?

Answer 32

• RCTs suggest a low
  incidence <5%
• Observational studies
  suggest 10-15%
• Clinic data puts it as
  high as 30%

Question 33

Other causes of statin intolerance

Answer 33

Question 34

Assessing Statin Intolerance - SAMS